We know that many traumatic brain injuries (TBIs) can be devastating. An important research topic is predicting what the effect a TBI of a particular type and severity will have on neuropathology and behavior.

Neuropathology is relatively easier to measure, but it is still hard to tell causality because a lot of the “markers” of TBI seen on neuropathologic exam are also sometimes seen in individuals who never had a TBI. Although their degree or distribution might be different.

Behavioral effects of TBI are especially hard to measure because you need standardized measures across time in both TBI-affected and TBI-unaffected individuals, controlling for all of the other factors that are known to affect behavior. A tough nut to crack.

Shively et al. recently described their clever study to address the causality of neuropathologic changes in TBI.

They compared the postmortem brains from donors with schizophrenia treated with prefrontal leucotomy (n = 5; more than 40 years prior to death) to age-matched donors with schizophrenia who hadn’t undergone leuctomy (n = 5).

Leucotomy, an obsolete treatment for schizophrenia, involved traumatic interruptions of white matter axons in the prefrontal cortex via burr holes. Here is what the lesions look like on MRI:

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From Uchino et al., an MRI of a person with a history of prefrontal leucotomy shows bilateral frontal white matter lesions; PMID:11156773

These authors looked at cortical tissue slices cut in the coronal plane at the leucotomy site, as well as slices rostral and caudal to the site.

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Shively et al.; PMC5325841

Here were some of their findings:

  • They found phosphorylated tau in neurons and astrocytes in cortex adjacent to the leucotomy site in 5/5 of the donors treated with leucotomy, but not in the rostral/caudal sites or in the donors who did not have leucotomy.
  • The p-tau tended to be at sulcal depths or surrounding small blood vessels. This is similar to what is seen in CTE.
  • They also found amyloid beta depositions in the cortex near the leucotomy sites, but only in the 3/5 donors who had at least one APOE ε4 allele.

Overall, this is really nice study that allows us to see the effect of TBI-associated axon injury in humans in a precisely controlled manner. What we see is that it causes phosphorylated tau accumulations in a similar distribution to that of CTE.


One of the exciting alternatives to the amyloid immunotherapies in clinical trials for Alzheimer’s disease (AD) are anti-tau antibodies.

There are several of these drugs in earlier stages of development, although none that I know of in phase 3. To take two concrete examples, let’s focus in on BioGen’s two anti-tau immunotherapies:

  • BMS-986168/BIIB092 = an humanized IgG4 monoclonal antibody targeting extracellular tau
  • BIIB076 = a monoclonal antibody against both monomeric and fibrillar tau

Both of these drugs are also being tested in PSP, which is a relatively rare, classical familial tauopathy in a way that AD isn’t — because in PSP, the 1-5% of familial cases are known to be caused by certain MAPT mutations. Whereas I don’t know of well-validated genetic mutations in MAPT that are associated with increased risk of Alzheimer’s, except for some preliminary reports of small statistical associations, such as this one.

To try to force myself to be accountable and quantitative, what is my prediction for the probability that each of these two drugs will be approved by the FDA by the end of 2025? Same rules and disclosures as my previous post about this, but two years extended because these drugs are in earlier stages of development.

I’m going with 2.5% for BIIB092 (in phase II) and 1.5% for BIIB076 (still in phase I). Clearly abnormalities in tau proteins are highly associated with pathogenesis in AD, indeed more strongly associated than Aβ, and there have been a number of suggestions that the tau abnormalities are causal.

But in my opinion, we don’t know for sure yet that these tau abnormalities are truly causal, and that stopping tau aggregation will be helpful.

On one hand, if an anti-tau antibody works, why shouldn’t an anti-NFL antibody, or any of the other proteins that are markers of axonal damage in AD and are inversely associated with cognitive status? Maybe they all would, but this thought experiment is a bit troubling to me.

On the other hand, anti-tau antibodies have already been shown to be helpful in an APP-overexpressing AD mouse model, improving both cognitive function and the proportion of mushroom dendritic spines.

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Castillo-Carranza et al 2015 Fig 1D; TOMA = anti-tau oligomer-specific monoclonal antibody, Tg2576 = APP-overexpressing AD mutant mouse; http://www.jneurosci.org/content/35/12/4857.long

It is asking a lot, but I would be more confident about the clinical relevance of this type of mouse study if it were shown that immunotherapies against other protein markers of axon damage, such as anti-NFL antibodies, were not successful in ameliorating cognitive decline, as a negative control.

Certainly I will be rooting for these anti-tau drugs to be successful in clinical trials and I think they make a lot of sense, but like most AD drugs in development, my prediction is that they are a long shot.

Idiopathic normal pressure hydrocephaus (NPH) is a diagnosis of occult hydrocephalus with normal CSF pressure on LP that was first described in 1965 and is often considered one of the treatable causes of dementia.

The original paper used the now uncommon brain imaging technique of pneumoencephalography, which involved draining the CSF, injecting air as a contrast medium, and performing a brain xray:

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Figure 2 from Adams et al 1965 showing uniformly enlarged ventricles; doi: 10.1056/NEJM196507152730301

At my med school we learned NPH by the triad of “wet, wobbly, and wacky”, referring to its classic triad of symptoms: urinary incontinence, gait disturbance, and cognitive impairment.

Like many symptom triads, these symptoms are non-sensitive, with the full triad seen in <60% of patients. It is also non-specific, as urinary incontinence is seen in ~20-40% of those over 60, gait impairment is seen in ~20% over those over 75, and mild cognitive impairment is seen in ~35% of those over 70.

Espay et al explain all of this in the introduction of their critical literature review of idiopathic NPH. One of their major points is that ventricle enlargement is also non-specific, as it is common in other neurodegenerative diseases such as AD, DLB, and PSP.

Here are some of their other points:

  • There are no specific clinical, imaging, or neuropathologic findings in NPH.
  • The determination of ventricle enlargement on MRI is subjective and not standardized.
  • A “true” diagnosis is dependent upon a treatment response to CSF diversion via a ventriculoperitoneal shunt (VPS), which is circular and problematic.
  •  There has never been a well-defined RCT to evaluate the use of VPS in NPH.
  • Because many patients diagnosed with NPH may in fact have NPH that is secondary rather than a precursor to other neurodegenerative diseases, the fact that VPS may lead to short-term cognitive amelioration even in these patients suggests that VPS should still be considered as a way to improve cognition even in patients that are diagnosed with these neurodegenerative diseases.

Overall, this paper is well worth a read for people interested in treatments for dementia.

Cells can die for a variety of reasons. Some of them are intentional (“programmed”) in response to exposure to external stressors (like viral or toxic molecules) or internal problems (like DNA damage). And some of them are unintentional (“non-programmed”), which often involves the premature breakdown of cell membranes and loss of cell contents.


The totally simple necroptosis cell death pathway, from the NIH via Wikipedia

Caccamo et al recently published a paper suggesting that one specific type of programmed cell death, necroptosis, might be a key part of what mediates neuron death in Alzheimer’s disease (AD).

Their evidence spanned multiple human data sets of postmortem AD brains and mouse models (5XFAD), and showed that markers for necroptosis (MLKL, RIP1, RIP3) were often significantly correlated with the degree of AD neuropathology seen in those brains.

Notably, their data didn’t provide strong evidence to exclude apoptosis and non-necroptosis necrotic cell death pathways as also contributory to cell death in AD.

So, another study that would also be interesting would be to see a more global comparison of all different types of cell death, to see which markers correlate the strongest with AD neuropathologic changes.

On the other hand, the authors note in their discussion that there is a lot of cross-talk between necrosis and apoptosis, which means that it may be difficult or not make sense to distinguish between them in this way.

Even if necroptosis is the mechanism of cell death in AD, that doesn’t mean that we can just turn off this cell death pathway and rescue neurons and memory. If anything, it suggests that the neurodegeneration itself is intentional, likely helpful to mitigate even more damage, and that changes to stop AD will have to occur much farther up to pathogenic cascade.

Still, it’s critical to understand exactly what is the pathway of degeneration in AD so that we can figure out what to target, and this study might be an important part of that.

A cerebral arteriovenous malformation (AVM) is an abnormal set of direct connections between the arteries and veins in the brain. These can cause a variety of neurologic symptoms, especially if they are large, and especially if they rupture.


arteriovenous malformation in the great cerebral vein of Galen; from Wikipedia user Filip em via Dr Laughlin Dawes

Mohr et al. recently published the result of the ARUBA trial, which compared medical (i.e., medical treatment for symptoms as needed) to interventional (i.e., surgical) treatment of this condition.

Their intention-to-treat analysis favored event-free survival in the medical management (MM; red) group:

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Mohr et al 2017; doi: 10.1212/WNL.0000000000004532

The actually-treated analysis favored event-free survival in the medical management (MM) group even more strongly:

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Mohr et al 2017; doi: 10.1212/WNL.0000000000004532

The authors suggest on the basis of this data that a reasonable management approach for unruptured cerebral AVM is to wait to see if a hemorrhage occurs, which may be mild if it does occur, and only then consider surgical intervention.

Many articles include the premise that Alzheimer’s disease (AD) neuropathology is unique to humans. However, there is a large body of literature suggesting that the characteristic neuropathology of AD, including diffuse amyloid plaques, neuritic amyloid plaques, and abnormally phosphorylated tau, are also seen in some non-human primates.

One of the only exceptions where AD pathology has not been commonly reported is coexisting amyloid plaques and neurofibrillary tangles, although even this has been reported in one chimpanzee.

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Coexisting tau and amyloid immunoreactivity in the PFC of a 41-year old chimpanzee; PMC2573460

On the genetic level, tau is identical between chimps and humans, while APP is 99% identical.

It is not that surprising that chimps would have the most similar neuropathology as humans, because chimps (and bonobos) are among the most similar non-human primates to humans.

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cladogram based on morphology and genetics from http://anthro.palomar.edu/primate/prim_8.htm

Now, a nice article from Edler et al examines neuropathology from 20 chimpanzees aged 37-62 to directly interrogate the presence of AD neuropathology in a large sample.

The authors scored neuropathology in all 20 chimpanzees in 4 brain regions (PFC, MTG, CA1, CA3) using the following scoring system:

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Here were some of their findings:

  • All of the chimps had APP/Aβ and Aβ-positive blood vessels, while only 2/3rds had plaques not associated with vessels, suggested that Aβ accumulation near blood vessels may be an early or precursor lesion in chimps.
  • Cerebral amyloid angiopathy, which is seen in 80% of AD patients, had a strong association with tau pathology in their chimps, especially pretangle density:
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CAA = Cerebral Amyloid Angiopathy; Fig 7B; PMID: 28888720

  • On the other hand, Aβ42 levels were not correlated with tau pathology.
  • Pretangle and NFT staining in chimps followed the pattern of Braak staging seen in humans.
  • In reviewing the literature, they note that only subtle, but not profound, age-related memory decline has been demonstrated in chimps. This may be because chimps have differences in APOE and other factors, but it is also the case that very few studies have directly addressed this question.

Overall, the most important finding from this study confirmed the previous 2008 report from a single chimp that amyloid and tau can coexist species other than humans.

These non-human primate studies shine an important light on the true biology of AD, which is especially important to consider when evolutionary or environmental explanations are invoked to explain the disease.

When I was reviewing the current clinical trials for Alzheimer’s disease (AD) a few months ago, I noted that the phase II trial of levetiracetam was particularly exciting — because if it works, it would require a massive reconceptualization in AD pathogenesis.

That’s mainly because levetiracetam is an anti-seizure medication, and focal seizures haven’t been traditionally associated with AD.

But our available tools for measuring focal seizures are quite poor — for example, they only cover a very small portion of the brain, mostly at the surface. So it is quite possible that AD pathogenesis could involve localized seizures early in the disease process, especially in a “buried” brain region like the hippocampus.

Now, Lam et al have provided some more evidence for the microseizure/focal memory-associated seizure hypothesis in AD, with a case report on two patients, both of whom were experiencing early stages of memory loss.

For both of these patients, the team used a minimally invasive surgical technique to place medial temporal electrodes for monitoring, which has been described in several previous studies including a 2005 study from Zumsteg et al that has a nice diagram:

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Localization of medial temporal lobe/foramen ovale (FO) electrode; https://doi.org/10.1016/j.clinph.2005.08.009

(Note that the hippocampus, that old memory-associated stalwart, is in the medial temporal lobe.)

One of the patients that Lam et al were treating had evidence of recurrent subclinical seizures in the medial temporal lobe (MTL), which were more prevalent during sleep.

Remarkably, treating her with 1500 mg/d of levetiracetam led to abrogation of the seizures, and she had only “mild progression” of her cognitive deficits.

Intriguingly, when she missed several doses of levetiracetam, she noticed a confusion spell. But like anything, this could just be correlation — maybe she missed doses because of worsening AD pathophysiology in that time period, and the confusion spell was an exaggerated symptom of this. Missing doses is certainly not a formal crossover or washout study. Still, intriguing.

The other patient that Lam et al were treating also had frequent MTL seizure activity that was exacerbated during sleep, as well as classic symptoms of early onset AD (eg, CSF pTau levels of 73.2 pg/ml).

Unfortunately, levetiracetam was not tolerated in this second patient, which the authors state was “owing to worsening mood.”

It would be great news if early AD pathophysiology were related to seizures, even in a subset of patients, because we already have drugs to treat seizures. So I agree with the authors that more research is certainly needed in this area.

That said, the evidence so far is certainly interesting, but far from definitive. Something like this study, but with a sample size of 10-20 and good correlations of MTL seizure activity with cognitive decline and/or confusion episodes, would be a great next step.

It would also be nice to know how common MTL seizure activity is during sleep in asymptomatic elderly people.